Abstract Background and Aims The management of anemia in hemodialysis patients (HD-ps) is influenced by many factors, including inflammation, martial balance (MB) and mineral metabolism (MM). Recent data would identify the Erythropoietin Resistance Index (ERI) as an indicator of mortality risk in HD-ps. The objective of the present study was to evaluate the relationship of ERI with inflammation, MB and MM, as well as all-cause mortality in a cohort of HD-ps. Method An observational-retrospective study was performed on 100 HD-ps, excluding those with acute or chronic infections (3 months), neoplasia, or immunosuppressive therapy. Mortality was considered primary outcome along a 2-year follow-up (FU). Results HD-ps, predominantly males, had advanced mean age, good Hb values and fair biochemical control. ERI showed significant correlations with some elements of inflammation, MM and BM (Table 1), including c-terminal fragment of Fibroblast Growth Factor 23 (cFGF23). At multivariate, ERI remained influenced by cFGF23 (p = 0.009), iron (p = 0.002) and transferrin (p = 0.007). Furthermore, after 2 years of FU, 42% of HD-ps died. As shown in Table 2, HD-ps that faced the primary outcome (death) were older, had lower levels of albumin, hemoglobin and transferrin, and higher levels of IL6, parathormone (PTH), reactive C protein (PCR), and ERI (p < 0.035). In multivariate, ERI (p = 0.011), age (p = 0.001) and albumin (p = 0.010) remained significant for the outcome studied. Conclusion Our data, albeit on few HD-ps, show a possible association between ERI and mortality. ERI was found to be related to several factors, including cFGF23, itself a factor implicated in maintaining a baseline inflammatory state. The results suggest the possible presence of some pathological mechanisms that can act silently with a negative impact on survival. Certainly, increased numbers and a prospective design could better clarify the explored relationships in the future.